1. Field of the Invention
The present invention relates to compositions including bisphosphonate pharmaceuticals having reduced GI toxicity due to the bisphosphonate pharmaceuticals and enhanced bio-availability of bisphosphonate pharmaceuticals after ingestion with food. The present invention also relates to the compositions to treat osteoporosis, methods for treating osteoporosis and methods for preparing the compositions.
More particularly, the present invention relates to compositions including a bisphosphonate and a zwitterionic phospholipid, where the compositions can be taken with meals, have reduced bisphosphonate GI toxicity and/or side-effects and have improved bisphosphonate bio-availability after ingestion with food. The present invention also relates to the compositions to treat osteoporosis, methods for treating osteoporosis and methods for preparing the compositions.
2. Description of the Related Art
Bisphosphonates represent a class of drugs that have shown very promising therapeutic efficacy in the treatment of a number of diseases associated with abnormally accelerated bone resorption including; osteoporosis, Paget's disease and hypercalcemia of malignancy. See e.g., Fleisch H., Ann Med, 29, 55-62 (1997) and Fleisch H.,Drugs, 42, 919-944 (1991). As an increasing number of these drugs become available for clinical use in the treatment of the millions of individuals with these skeletal diseases, evidence is becoming available that their chronic usage may be associated with a number of gastrointestinal side-effects, such as diarrhea, abdominal pain and inflammation (e.g. esophagitis and gastritis), erosions and ulceration of the upper gastrointestinal tract. See e.g., Maconi G, Bianchi Porro G., Am J Gastroenterol, 90, 1889-1890 (1995); Lufkin E G, Argueta R, Whitaker M D, Cameron A L, Wong V H, Egan K S, O'Fallon W M, Riggs B L, Osteoporos Int, 4, 320-322 (1994); De Groen P C, Lubbe D J, Hirsch I J, Daifotis A, Stephenson W, Freedholm D, Pryor-Tillotson S, Seleznick M J, Pinkas H, Wang K K, N Eng J Med, 335, 1016-1021 (1996). Women, five or more years past the onset of menopause, who are in an estrogen-deficient state, are particularly prone to developing osteoporosis and are also at greatest risk of developing GI side-effects when placed on chronic bisphosphonate therapy.
It has been estimated that 8-10 million Americans are suffering from osteoporosis and an additional 17-20 million of our populace have low bone mass, placing them at risk for this disease. Women constitute ˜80% of this “at risk” population. In many cases, these individuals are also taking non-steroidal anti-inflammatory drugs (NSAIDs) to alleviate the pain and inflammation of arthritic joints, further compounding their risk of developing GI complications. In confirmation with these clinical observations, Graham and associates performed a number of endoscopic studies on healthy subjects taking the bisphosphonate, alendronate, for a period up to 2 weeks at doses recommended for the treatment of Paget's Disease (40 mg) or osteoporosis (10 mg) and reported that 40-60% of the volunteers had observable gastric erosions, while 10-20% developed one or more gastric ulcers. See e.g., Graham D Y, Malaty H M, Goodgame R, Am J Gastroenterol, 92, 1322-1325 (1997) and Graham D Y, Malaty H M, Aliment Pharmacol Ther, 13, 515-519 (1999). In support of these concerns, Lanza reported that alendronate (Fosamax) administered at both at 10 mg and 40 mg doses significantly retarded the rate of healing of aspirin-induced gastric erosions. See e.g., Lanza F L, Am J Gastroenterol, 91, 1916 (1996).
In order to investigate the potential mechanism of GI damage due to bisphosphonates under more controlled experimental conditions, a number of laboratories have developed animal models of this condition. Peter et. al. recently compared the chronic effects of increasing doses of alendronate, risedronate and etidronate administered over a 4 week period in rats and reported that all three bisphosphonates induced a dose-dependent injurious effect on mucosae of the gastric body and antrum. The dose-dependent injurious effects were observed both macroscopically and histologically, along with evidence of submucosal inflammation. See e.g., Peter C P, Kindt M V, Majka J A, Dig Dis Sci, 43, 1009-1015 (1998).
Blank et al. developed an acute model of bisphosphonate-induced gastric injury in rats that were intragastrically administered high doses of the bisphosphonates alone or in combination with the NSAID, indomethacin. See e.g., Blank M A, Ems B L, Gibson G W, Myers W R, Berman S K, Phipps R J, Smith P N, Dig Dis Sci, 42, 281-288 (1997). In these studies, they demonstrated that although the bisphosphonates or the NSAID induced little or no observable macroscopic gastric lesions over the 4 hr study period, concomitant treatment with two classes of drugs resulted in the development of gastric ulcers, along with evidence of mucosal necrosis and inflammatory infiltration of the submucosa. Using this model, they compared several compounds and concluded, contrary to the findings of Peter et al., that the bisphosphonates with a primary amino group (pamidronate and alendronate) were more irritating to the gastric mucosa than those containing a fixed nitrogenous group (risedronate and NE-97221).
Elliott et. al. also employed this rodent model to demonstrate that in combination with indomethacin, only bisphosphonates administered intragastrically (vs. intraperitoneal administration) induced gastric injury, and in a related experiment demonstrated that alendronate significantly delayed the healing of experimentally induced gastric ulcers in rats. See e.g., Elliott S N, McKnight W, Davies N M, MacNaughton W K, Wallace J L, Life Sci, 62, 77-91 (1998). Moreover, many bisphosphonates have low bio-availability requiring patients to routinely ingest large doses of the bisphosphonate to get a desired benefit with concurrent increased risk of GI adverse side effects.
Thus, it would be an advancement in the art to have bisphosphonate formulations that reduce or eliminate the adverse effects of bisphosphonates on the upper GI tract, while allowing the bisphosphonates to be taken with meals and thereby increasing the bio-availability of the bisphosphonate when taken with food.